CD74

Official Full Name

CD74 molecule

Organism

Homo sapiens

GeneID

972

Background

The protein encoded by this gene associates with class II major histocompatibility complex (MHC) and is an important chaperone that regulates antigen presentation for immune response. It also serves as cell surface receptor for the cytokine macrophage migration inhibitory factor (MIF) which, when bound to the encoded protein, initiates survival pathways and cell proliferation. This protein also interacts with amyloid precursor protein (APP) and suppresses the production of amyloid beta (Abeta). Multiple alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2011]

Synonyms

II; p33; CLIP; DHLAG; HLADG; Ia-GAMMA;

Protein Sequence

MHRRRSRSCREDQKPVMDDQRDLISNNEQLPMLGRRPGAPESKCSRGALYTGFSILVTLLLAGQATTAYFLYQQQGRLDKLTVTSQNLQLENLRMKLPKPPKPVSKMRMATPLLMQALPMGALPQGPMQNATKYGNMTEDHVMHLLQNADPLKVYPPLKGSFPENLRHLKNTMETIDWKVFESWMHHWLLFEMSRHSLEQKPTDAPPKVLTKCQEEVSHIPAVHPGSFRPKCDENGNYLPLQCYGSIGYCWCVFPNGTEVPNTRSRGHHNCSESLELEDPSSGLGVTKQDLGPVPM

Open

Disease

Lupus erythematosus, Mature B-cell leukaemia

Approved Drug

Clinical Trial Drug

1 +

Discontinued Drug

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Detailed Information

The CD74 gene encodes a protein that plays a pivotal role in immune response through its interactions with the Class II Major Histocompatibility Complex (MHC II). Functioning as a cell surface receptor for the cytokine Macrophage Migration Inhibitory Factor (MIF), it controls antigen presentation as a fundamental chaperone. MIF's attachment to CD74 triggers survival mechanisms and accelerates cell division. Furthermore tying CD74 to Alzheimer's disease pathogenesis is its interaction with amyloid precursor protein (APP), which reduces the generation of amyloid-beta (Aβ). The gene shows alternative splicing, generating many isoforms and adding to its functional variety.

Structure of CD74

CD74 is a type II transmembrane protein, meaning its N-terminus faces the cytosol. Two main isoforms are present in humans: p33 and p41. While the p33 isoform is much shorter, the p41 isoform has an extra exon 6b inside its luminal region. Isoforms in mice match p31 and p41. Two more variants arising from alternate start codons—p35 and p43—extend the N-terminus by 16 amino acids. Among the many post-translational changes the protein experiences are N- and O-glycosylation, phosphorylation, and S-acylation. These changes affect its operation, traffic, and stability. Particularly, palmitoylation of CD74 influences its stability and processing; the precise physiological function of this alteration is still unknown.

Function of CD74 in Antigen Presentation

Crucially important in the adaptive immune response, CD74 is necessary for the processing and presentation of antigens via MHC II. Found on antigen-presenting cells (APCs) including dendritic cells, macrophages, and B cells are MHC II molecules. Through stabilization of peptide-free MHC II dimers and direction towards endosomal/lysosomal compartments where antigen processing takes place, CD74 helps MHC II molecules to assemble. CD74 inhibits the peptide-binding site of MHC II throughout this process, therefore stopping early peptide binding. HLA-DM releases CD74 as the complex reaches the endosome, therefore enabling the binding of antigenic peptides to MHC II.

Figure 1 describes the role of CD74 in the MHCII antigen presentation pathway, including its interaction with MHCII, antigen processing and trafficking, and the degradation of CD74, leading to the release of an intracellular domain that may influence transcriptional regulation. Figure 1. The role of CD74 in the MHCII antigen presentation pathway. (Schröder B., 2016)

In addition to its role in MHC II-mediated antigen presentation, CD74 is also engaged in cross-presentation—exogenous antigens are delivered via MHC class I. Because of ineffective targeting of MHC class I complexes to the endosomal/lysosomal compartments, the cross-priming capacity is much reduced in CD74-deficient dendritic cells.

Role of CD74 in Immune Signaling and Pathogenesis

Apart from its function in antigen-presenting, CD74 is engaged in other cellular activities. Key in immunological signaling, especially in response to inflammatory cytokines such as IFN-γ, which causes CD74 expression in numerous cell types including epithelial and endothelial cells. Linking it to cellular stress reactions, CD74 attaches to MIF, which then triggers survival and proliferation pathways.

Recent research further underlines CD74's antiviral action, especially against viruses such as SARS-CoV-2 and Ebola and coronaviruses. Because it disturbs the processing of viral glycoproteins, the p41 isoform of CD74 is especially important for preventing viral entrance. This ability highlights the variety of functional repertoire of the protein as it differs from its involvement in antigen presentation.

Interactions and Post-Translational Modifications

CD74 interacts with several of the proteins involved in immune responses. It links, for example, with the transmembrane area of MHC II to stabilize the MHC II complex and enable its movement to the endosomal compartments. Furthermore, interacting with other signaling molecules, CD74 influences pathways including signal transduction, endocytosis, and cell migration.

Moreover essential for the function of CD74 is phosphorylation of it. Research has shown that serine residue phosphorylation in the cytoplasmic domain influences CD74's capacity to access antigen-processing compartments and leave the endoplasmic reticulum (ER). Particularly, phosphorylation of the p35 isoform improves its trafficking to the endosome, therefore highlighting the significance of post-translational changes in control of CD74's activity.

CD74 in Disease Pathogenesis

CD74 is implicated in several diseases. For example, it has been connected to autoimmune disorders such as rheumatoid arthritis, where its participation in antigen presentation could affect the course of the condition. Moreover, linked to malignancies is CD74, including mucinous lung adenocarcinoma. Connected to Alzheimer's disease, where it helps to lower amyloid-beta generation, which is a characteristic of the condition, CD74 interacts with amyloid precursor protein (APP).

References:

Schröder B. The multifaceted roles of the invariant chain CD74--More than just a chaperone. Biochim Biophys Acta. 2016;1863(6 Pt A):1269-1281.
Borghese F, Clanchy FI. CD74: an emerging opportunity as a therapeutic target in cancer and autoimmune disease. Expert Opin Ther Targets. 2011;15(3):237-251.
Su H, Na N, Zhang X, Zhao Y. The biological function and significance of CD74 in immune diseases. Inflamm Res. 2017;66(3):209-216.

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